Defective morphogenesis and functional maturation in fetal islet-like cell clusters from OLETF rat, a model of NIDDM
1Research Institute for Children, Children's Hospital, Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans 70112, USA.
Abstract:
A failure in the compensate proliferation of pancreatic beta-cells, as the primary pathogenic event, has been reported in OLETF rat, a model of NIDDM. The aim of the present study is to define whether the beta-cell defect is attributed to the fetal stage islet development, if so, whether the defect involves down regulation of PDX-1 protein expression. Morphological changes, beta-cell function, and the expression of PDX-1 protein were examined in the cultured fetal islet-like cell clusters (ICCs) from OLETF rats along with their diabetes-resistant control counterpart LETO rats in the presence of 5.5 or 11.1mM glucose for 48, 72, 96, and 120-hr, respectively. We have observed four abnormalities in the ICCs of OLETF rats. First, a defective morphogenesis was noted during the 72 to 120-hr ICC culture, a period characterized by a dramatic increase in both beta-cell and non-beta-cell (alpha, delta, and PP) populations in control rats. This defective morphogenesis was demonstrated by a growth retardation of epithelial stratification and poor development of both beta-cell and non-beta-cell masses along with a parallel decline in relevant islet hormone contents. Second, a functional defect was characterized by failure to response to glucose during the 96 to 120-hr-cultured ICCs. Third, the ultrastructural analysis revealed a significant reduction in the number of secretory granules. Four, Western blot analysis showed a significant decrease of PDX-1 protein expression in the OLETF ICCs cultured in 11.1mM glucose for 48 to 72-hr and in 5.5mM glucose for 120-hr. Therefore, we concluded that during the fetal stage of islet development, OLETF rats exhibit both morphological and functional defects.
Insights
Pancreatic beta-cell defects in OLETF rats, a model for non-insulin-dependent diabetes mellitus (NIDDM), originate during fetal development. These defects include impaired islet morphogenesis, reduced glucose responsiveness, and decreased PDX-1 protein expression.
Area of Science:
- Endocrinology
- Developmental Biology
- Diabetes Research
Background:
- Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by impaired pancreatic beta-cell function.
- OLETF rats, a model for NIDDM, exhibit a failure in compensatory beta-cell proliferation.
- The precise developmental origin of beta-cell defects in OLETF rats remains unclear.
Purpose of the Study:
- To investigate whether beta-cell defects in OLETF rats are attributable to fetal islet development.
- To determine if impaired PDX-1 protein expression is involved in these fetal-stage defects.
Main Methods:
- Cultured fetal islet-like cell clusters (ICCs) from OLETF and control LETO rats.
- Assessment of morphological changes, beta-cell function (glucose response), and PDX-1 protein expression.
- Utilized varying glucose concentrations (5.5mM, 11.1mM) and culture durations (48-120 hours).
Main Results:
- OLETF ICCs displayed defective morphogenesis, characterized by growth retardation and reduced cell mass.
- Impaired glucose responsiveness was observed in OLETF ICCs after 96-120 hours of culture.
- Significant reduction in PDX-1 protein expression was detected in OLETF ICCs under specific glucose conditions.
Conclusions:
- OLETF rats exhibit morphological and functional defects in islet development during the fetal stage.
- Downregulation of PDX-1 protein expression is associated with these fetal-stage beta-cell abnormalities.
- These findings highlight the critical role of fetal islet development in the pathogenesis of NIDDM in OLETF rats.
